U.S. patent number 5,792,474 [Application Number 08/362,592] was granted by the patent office on 1998-08-11 for process for the production of retarded pharmaceutical compositions.
This patent grant is currently assigned to Goedecke Aktiengesellschaft. Invention is credited to Roland Rauchfuss.
United States Patent |
5,792,474 |
Rauchfuss |
August 11, 1998 |
Process for the production of retarded pharmaceutical
compositions
Abstract
According to the present invention, there is provided a
continuous method for the production of retarded pharmaceutical
compositions by an extrusion process. A mixture of an active
material, a low and high melting lipid or lipoid components is
introduced by means of an extruder screw conveyor into a preheated
extruder and brought to a temperature which is at most about
4.degree. C. above the melting temperature of the low melting
component at a pressure of about 200 to about 600 kPa(N/m.sup.2).
The mass is extruded through a nozzle plate with a nozzle diameter
of about 1.2 to about 4 mm and subsequently cooled, and if desired,
granulated.
Inventors: |
Rauchfuss; Roland (Freiburg,
DE) |
Assignee: |
Goedecke Aktiengesellschaft
(Berlin, DE)
|
Family
ID: |
6459487 |
Appl.
No.: |
08/362,592 |
Filed: |
June 16, 1995 |
PCT
Filed: |
May 21, 1993 |
PCT No.: |
PCT/EP93/01289 |
371
Date: |
June 16, 1995 |
102(e)
Date: |
June 16, 1995 |
PCT
Pub. No.: |
WO93/24110 |
PCT
Pub. Date: |
December 09, 1993 |
Foreign Application Priority Data
|
|
|
|
|
May 22, 1992 [DE] |
|
|
42 16 948.8 |
|
Current U.S.
Class: |
424/489; 424/449;
424/468; 424/470; 424/490; 424/491 |
Current CPC
Class: |
A61K
9/1617 (20130101); A61K 9/2013 (20130101); A61K
9/1694 (20130101) |
Current International
Class: |
A61K
9/16 (20060101); A61K 9/20 (20060101); A61K
009/14 () |
Field of
Search: |
;424/470,489,490,488,449,452 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
Primary Examiner: Phelan; D. Gabrielle
Assistant Examiner: Benston, Jr.; William E.
Attorney, Agent or Firm: Atkins; Michael J.
Claims
What is claimed is:
1. Process for the production of a pharmaceutical composition with
retarded liberation of active material comprising the steps of:
(a) mixing the active material not only with a high melting lipid
or lipoid component but also with a low melting lipid or lipoid
component, the weight ratio of the two lipid or lipoid components
being in the range of about 1:5 to about 5:1;
(b) introducing the resulting mixture by means of an extruded screw
conveyor into a preheated extruded;
(c) bringing the resulting mixture of active material and lipid or
lipoid components to a temperature which lies above the melting
point of the low melting component but below the melting point of
the high melting component, the temperature being at most 40 C
above the melting temperature of the low melting component, the so
heated mixture being subject to a pressure of about 200 to about
600 kPa(Nm.sup.2), the active material and the high melting
component thereby being uniformly dispersed in the completely
molten low melting component and extruded through a nozzle plate
with a nozzle diameter of about 1.2 to about 4 mm;
(d) allowing the resulting mixture, after melting of the low
melting component to cool to below the melting point thereof,
and
(e) granulating the resulting mixture during the cooling or
thereafter.
2. Process according to claim 1 wherein the diameter of the screw
conveyor is about 50 mm.
3. Process according to claim 1, wherein the temperature according
to (d) is a working temperature of about 58.degree. to about
60.degree. C.
4. Process for the production of a pharmaceutical composition with
retarded liberation of active material comprising the steps of:
(a) mixing the active material not only with a high melting lipid
or lipoid component but also with a low melting lipid or lipoid
component, the weight ratio of the two lipid or lipoid components
being in the range of about 1:5 to about 5:1;
(b) introducing the resulting mixture by means of an extruder screw
conveyor into a preheated extruder;
(c) bringing the resulting mixture of active material and lipid or
lipoid components to a temperature which lies above the melting
point of the low melting component but below the melting point of
the high melting component, the temperature being about 1 to about
30 C above the melting temperature of the low melting component,
the so heated mixture being subjected to a pressure of about 200 to
about 600 kPa (N/m.sup.2), the active material and the high melting
component thereby being uniformly dispersed in the completely
molten low melting and extruded through a nozzle plate with a
nozzle diameter of about 1.3 to about 3 mm;
(d) allowing the resulting mixture, after melting of the low
melting component to cool to below the melting point thereof;
and
(e) granulating the resulting mixture during the cooling or
thereafter.
5. Process according to claim 4, wherein the temperature according
to (d) is about 1.degree. to about 2.degree. C. above the melting
temperature of the low melting lipid or lipoid component.
6. Process according to claim 4, wherein the nozzle diameter in the
nozzle plates is about 1.5 to about 2 mm.
7. Process according to claim 4, wherein the speed of rotation for
the extruder is in the range from about 170 to about 180 rpm.
8. Process according to claim 4, wherein the screw conveyor length
is about 1200 mm.
9. Process according to claim 4, wherein the diameter of the screw
conveyor is about 50 mm.
10. Process according to claim 4, wherein the temperature according
to (d) is a working temperature of about 58.degree. to about
60.degree. C.
11. Process for the production of a pharmaceutical composition with
retarded liberation of active material comprising the steps of:
(a) mixing the active material not only with a high melting lipid
or lipoid component but also with a low melting lipid or lipoid
component, the weight ratio of the two lipid or lipoid components
being in the range of about 1:5 to about 5:1;
(b) introducing the resulting mixture by means of an extruder screw
conveyor into a preheated extruder;
(c) bringing the resulting mixture of active material and lipid or
lipoid components to a temperature which lies above the melting
point of the low melting component but below the melting point of
the high melting component, the temperature being at most about 1
to about 20 C above the melting temperature of the low melting
component, the so heated mixture being subjected to a pressure of
about 200 to about 600 kPa (N/m.sup.2), the active material and the
high melting component thereby being uniformly dispersed in the
completely molten low melting and extruded through a nozzle plate
with a nozzle diameter of 1.5 to 2 mm;
(d) allowing the resulting mixture, after melting of the low
melting component to cool to below the melting point thereof;
and
(e) granulating the resulting mixture during the cooling or
thereafter.
12. Process according to claim 11, wherein the speed of rotation
for the extruder is in the range from about 170 to about 180
rpm.
13. Process according to claim 12, wherein the screw conveyor
length is about 1200 mm.
14. Process according to claim 13, wherein the diameter of the
screw conveyor is about 50 mm.
15. Process according to claim 14, wherein the temperature
according to (d) is a working temperature of about 58.degree. to
about 60.degree. C.
Description
This application is a 371 of PCT/EP93/01289 filed May 21, 1993.
FIELD OF THE INVENTION
The present invention is concerned with a process for the
production of pharmaceutical compositions with retarded liberation
of active materials. More specifically, a mixture of an active
material, and a low and high melting lipid or lipoid components are
introduced by means of an extruder screw conveyor into a preheated
extruder and brought to a temperature which is at most 4.degree. C.
above the melting temperature of the low melting component at a
pressure of 200 to 600 kPa (N/m.sup.2). The mass is extruded
through a nozzle plate with a nozzle diameter of 1.2 to 4 mm and
subsequently cooled and, if desired, granulated.
BACKGROUND
From EP0 043,254 is a known process for the production of
pharmaceutical compositions with a retarded release of active
materials which is based upon a selective melting process of at
least two lipid or lipoid components which have a retarding action
for pharmaceutically active materials mixed with these components.
Retarded release, or a more commonly referred to as sustained
release, concerns the timed control of the liberation of active
materials from active-material containing compositions and
especially from pharmaceutical compositions. Retarded release
compositions, therefore, achieve a prolongation of the period of
action and avoid too quick and/or too concentrated a release of the
active materials in the compositions, and too high of peaks of the
blood or tissue levels, which can lead to undesirable side
effects.
The process is characterized in that
(a) the active material is finely divided;
(b) the active material in finely divided form is mixed not only
with a finely divided, high melting lipid or lipoid component but
also with a finely divided, low melting lipid or lipoid component,
the weight ratio of the two lipid or lipoid components thereby
being in the range of from 1:5 to 5:1;
(c) the resulting mixture of active material and lipid or lipoid
components is brought to a temperature which lies above the melting
point of the low melting component but below the melting point of
the high melting component, the active material and the high
melting lipid or lipoid component thereby being uniformly dispersed
in the molten low melting lipid or lipoid component;
(d) after the melting of the low melting component, the resulting
mixture is allowed to cool below the melting point thereof; and
(e) during the cooling or thereafter, the resulting mixture is
granulated, the statements "low melting" and "high melting" thereby
being used with reference to the relationship to one another
without including any particular melting points.
Although it has already proved to be technically useful, the said
process has certain disadvantages which, in particular, impede a
continuous and automatically controlled production process. Thus,
hitherto, it has not been possible to carry out the melting process
continuously. In the Patent Specification, it is admittedly
suggested, inter alia, to bring about the melting of the low
melting component solely by means of the frictional heat of an
extruder and, in this way, to omit a separate heating of the
mixture. However, experiments recently carried out have shown that
the frictional heat of an extrusion process is not sufficient
completely to melt the low melting component. Therefore, the
extrudate obtained is inhomogeneous and cannot be used for the
granulation or other working up to give a medicament. Consequently,
hitherto it has not been possible homogeneously to extrude the
partly melted product. If, now, an attempt is made to increase the
frictional heat by increasing the speed of rotation of the screw
conveyor, then, without the working temperature increasing
substantially, surprisingly a demixing takes place and, due to an
extreme pressure increase in front of the nozzle plate, the
extruder is sometimes stressed as far as a material destruction
(breakage of the screw conveyor) without it having been possible to
achieve the desired effect. Consequently, according to EP0 043,254,
as previously, each batch must itself be mixed in appropriately
dimensioned vessels, heated and again cooled within a previously
determined period of time scheme. This is not only time-consuming
but is automatically involved with many empty runs for cleaning and
resupplying between the actual production batches. According to the
previous production process in a 114 kg capacity planet mixer, the
heating up time up to the melting range of 58.degree. to 60.degree.
C. itself amounted, for example, to 1 hour. Furthermore, the
material loss, i.e. the loss of active and adjuvant materials which
remain adhering to the walls of the vessel and which, as a rule,
are lost in the course of the cleaning process, is far from
negligible. A further disadvantage of the process is that, after
completion of the melting process, the final mixture is obtained in
large lumps or as a melt cake which must first be removed from the
melting vessel by manual shovelling and must then be comminuted
before the final retarded mixture can be transferred to a
granulator.
However, attempts to use an extruder with additional heating also
initially failed completely. Even with the supply of heat, it was,
namely, first not possible to produce an extrudate. Starting from
the obvious assumption that the very short residence time of 2 to 5
minutes of the mixture in the extruder required a high melting
temperature, as melting temperature there was chosen a temperature
range lying only slightly below the melting point of the high
melting component. As was to have been expected, the low melting
component was thereby melted but, at the same time, an unexpected
squeezing effect occurred which resulted in the low melting
component being separated from the remainder of the mixture and
being pressed in molten form through the nozzle plate. The mixture
remaining in the extruder was thus separated from the "lubricant"
and solidified. The frictional resistance thereby increased to such
an extent that the extruder was stopped. Attempts to overcome this
problem by a variation of the speed of rotation of the screw
conveyor or by reducing the diameter of the nozzle were
unsuccessful. A reduction of the temperature was not carried out
since, due to this means, only a further impairment of the results
was to have been expected. In the case of this consideration, it
was, in particular, taken into account that a lower melting
temperature would automatically undesirable prolong the period of
residence of the mixture in the extruder but the deleterious
squeezing out effect can, therefore, thereby not be favorably
influenced because, upon reaching the nozzle plate, the whole of
the low melting component must be present in a molten state and,
consequently, under the pressure of from 200 to 600 kPA (N/m.sup.2)
prevailing in the extruder, would be squeezed off just as in the
case of higher temperatures. Any kind of temperature influence on
the squeezing off effect was not to have been expected.
Furthermore, it was to have been expected that slow heating up and,
consequently, low temperatures in the heating up phase would not
only reduce the throughput but would also require a very long
compression path and thus expensive apparatus.
It is an object of the present invention to overcome the
above-mentioned disadvantages and to provide a fully automatic and
continuously operating melting process according to EP-PS 0 043
254.
SUMMARY
Surprisingly, we have now found that, contrary to expectations and
hitherto inexplicably, the harmful squeezing out effect in the case
of a simple reduction of the working temperature into the lowest
possible range disappears completely and that, consequently, the
mixture known from and suggested in EP0 043,254, in spite of the
many previously unsuccessful attempts, can, without special change
of the composition and especially without any additions for the
modification of the friction, be extruded to give extrudates which
are outstandingly suitable for further working up when the well
comminuted and pre-mixed powdered mass is subjected to an extrusion
process at a temperature which lies at most about 4.degree. C.
above the melting temperature of the low melting lipid or lipoid
component at a pressure of about 200 to about 600 kPa (N/m.sup.2)
and the partly melted and well mixed mass according to EP0 043,254
is extruded through a nozzle plate with a nozzle diameter of about
1.2 to about 4 mm.
BRIEF DESCRIPTION OF THE DRAWING
FIG. 1 is a cross-sectional elevation view of an extruder.
DETAILED DESCRIPTION OF THE INVENTION
According to the present invention, the temperature in the extruder
is to be not more than about 1.degree. to about 4.degree.,
preferably about 1.degree. to about 3.degree. and most preferably
only about 1.degree. to about 2.degree. C. above the melting
temperature of the low melting component. Thus, the temperature of
the heating mantle used must be correspondingly so adjusted that
these temperature ranges are maintained in the mixture to be worked
up over the whole length of the screw conveyor. Only shortly before
passing the nozzle can the temperature be lowered to the region of
the temperature of solidification of the low melting component
when, by means of a sufficient speed of conveying, care is taken
that this component can solidify only after passing the nozzle
plate.
However, even when the temperature lies in the above-given optimum
range, a usable, i.e. granulatable product which can be converted
into a pharmaceutical is only obtained when, at the same time, the
diameter of the nozzles is adjusted to a size adapted to the
process. If the nozzle diameter is less than about 1 mm, then the
nozzle plate becomes blocked up and the extruder is stopped by the
increasing friction, which can result in considerable damage to the
machine. If, on the other hand, the diameter is too great, i.e.
greater than about 4 mm, then a product is obtained which
admittedly appears to be usable but which, in actuality, is only
melted on the surface. There is, as it were, obtained a tube with a
melted-on wall and a powdered filling. Thus, here, too, it is
important to find the correct diameter range. This is about 1.2 to
about 4, preferably about 1.3 to about 3 and more preferably about
1.5 to about 2 mm.
The speed of rotation of the screw conveyor(s) is, corresponding to
the extruder used and to the mixture to be worked up, to be so
adjusted that the process pressure of about 200 to about 500 kPa
(N/m.sup.2) aimed for is achieved. A typical range of speed of
rotation for an extruder with a screw conveyor length of about 1200
mm is, in the case of a melt pressure of about 200 to about 600 kPa
(N/m.sup.2), from about 50 to about 200 rpm.
In comparison with the process known from the above-mentioned prior
art, the process according to the present invention possesses
considerable advantage. Due to the continuous method of production,
the finishing time for a unit amount can be considerably reduced.
For example, for the production of 450 kg of granulate hitherto 16
working hours were needed. By means of the process according to the
present invention, the same amount can be produced in only 4
working hours. The actual production time is thereby reduced by
about 50%. The extruder requires less space and operates very
economically. For example, with an extruder with a screw conveyor
length of only 1400 mm, 110 to 130 kg of extrudate can be produced
per hour.
The present invention will now be described in more detail with
reference to the accompanying FIG. 1. The following examples are
given for the purpose of illustrating the present invention, but
are not meant in any way to restrict the effective scope of the
invention.
EXAMPLES
From a storage container (1), a previously prepared, finely divided
mixture consisting of:
37.5 kg hydrogenated castor oil, m.p. 80.degree.-85.degree. C.
60.0 kg powdered stearic acid, m.p. 55.degree.-56.degree. C.
90 kg diltiazem hydrochloride
255.5 kg lactose K
1.5 kg magnesium stearate
1.75 kg carboxymethylcellulose
is passed via a dosing screw conveyor (2) to the actual extruder
(3). The extruder (3) is divided up into several temperable
sections (a-f) and is driven by a controllable motor (4). The
mixture is conveyed through the extruder (3) preheated by the
heatable mantle (5), at a speed of rotation of 170-180 r.p.m. The
diameter of the screw conveyor is 50 mm. In all sections, the
mantle temperature is 58.degree.-60.degree. C., which corresponds
to a working temperature of 58.degree.-60.degree.. After an average
period of residence of 2 to 4 minutes, the partly melted product is
extruded through a nozzle plate (6). The nozzle plate (6) contains
20 nozzle openings each with an inner diameter of 1.5 to 3 mm.
Under the described conditions, the apparatus conveys 110 to 120 kg
of extrudate per hour. The extrudate is cooled substantially to
ambient temperature in the form of fine, uniform strands on a
slowly moving conveyor belt and is subsequently passed to a
granulator (8). The final granulate finally reaches a collection
container (9). In the simplest case, the sections (a) to (f) are
uniformly tempered so that, in the case of passing through the
extrusion process, the same working temperature prevails over the
whole of the length of the screw conveyor (1400 mm). However, it is
also possible initially to work at a somewhat higher temperature
and gradually to decrease this until, possibly in the last section
(f), the working temperature has been reduced almost to the
solidification temperature of the low melting component. In this
way, the cooling phase is shortened somewhat without it resulting
in a blockage of the nozzles.
Otherwise, the mixtures described in EP0 043,254 can be used and
working up without alteration.
A batch for the production of 120 mg diltiazem compositions
contains, for example:
96 kg diltiazem hydrochloride
272 kg lactose K
40 kg hydrogenated castor oil
4.8 kg carboxymethylcellulose
65 kg stearic acid
1.6 kg magnesium stearate.
A batch for the production of 120 mg diltiazem compositions
contains, for example:
120 kg diltiazem hydrochloride
215.3 kg lactose K
64 kg stearic acid NF
40 kg hydrogenated castor oil
2.25 kg carboxymethylcellulose
2.25 kg magnesium stearate.
A batch for the production of 180 mg diltiazem compositions
contains, for example:
180 kg diltiazem hydrochloride
144.124 kg lactose K
48 kg hydrogenated castor oil
68.2 kg stearic acid NF
1.124 kg hydroxyethylcellulose
2.3 kg magnesium stearate.
A batch for the production of 240 mg diltiazem compositions
contains, for example:
13.5 kg lactose X
24 kg diltiazem hydrochloride
12 kg hydrogenated castor oil
10 kg stearic acid
0.175 kg hydroxyethylcellulose
0.4 kg magnesium stearate.
A batch for the production of norfenefrine compositions contains,
for example:
58.5 kg norfenefrine hydrochloride
152.1 kg lactose K
5.85 kg titanium dioxide
29.25 kg hydrogenated castor oil
43.876 kg stearic acid NF
2.924 kg carboxymethylcellulose.
A further batch for the production of norfenefrin compositions
contains, for example:
30 kg norfenefrine hydrochloride
166 kg lactose X
6 kg titanium dioxide
30 kg hydrogenated castor oil
44 kg stearic acid NF
4 kg carboxymethylcellulose.
While there have been described what are presently believed to be
the preferred embodiments of the invention, those skilled in the
art will realize that changes and modifications may be made thereto
without departing from the spirit of the invention, and it is
intended to claim all such changes and modifications as fall within
the true scope of the invention.
* * * * *